Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer death, with nearly all cases following a rapid and merciless course of intractable pain, cachexia, hopelessness and death. Repeated cycles of clinical trial failures have underscored the need for an improved understanding of PDAC pathogenesis, motivating the formation of this multi-disciplinary team of basic, translational and clinical scientists, with knowledge in cancer cell signaling, developmental and stem cell biology, tumor biology and angiogenesis, mouse models of cancer, genomics and informatics, molecular imaging, experimental pathology, and small molecule chemistry and biotherapeutics. The goal of this P01 is to further elucidate the genetics and biology of the disease to a level that will guide the rational development of effective targeted agents, alone and in combination. Specifically, we seek to (i) refine mouse models of human PDAC in order to understand the tumor biological role of PDAC signature mutations, (ii) identify, validate and characterize new human PDAC oncogenes in order to set the stage for drug discovery, (iii) illuminate and validate the role of the PI3K pathway in PDAC using mouse and human systems with the goal of identifying key therapeutic targets and guiding clinical trials targeting this pathway, (iv) utilize genetically engineered mice and human tumors to define signaling events governing the evolution and maintenance of the PDAC microenvironment, and to use this information to design and conduct innovative preclinical trials in refined mouse models of human PDAC, (v) determine the PDAC cell of origin and its genetic events in the mouse so as to illuminate a possible path to chemoprevention, and (vi) identify and characterize PDAC cancer stem cells in murine and human tumors. State-of-the-art imaging and antibody technologies, as well as strong experimental pathology and biospecimens repositories, will enable in-depth and dynamic analyses of PDAC tumor biology and signaling in unprecedented detail. The long-term goal of these basic and preclinical efforts, employing and integrating both mouse and human systems, is to identify and guide opportunities for targeted drug discovery and for the development of diagnostic agents and biomarkers.